Molecular pathways associated with BCC to SCC pathway switching

项目摘要/摘要： 基底细胞癌(BCC)是最常见的皮肤癌类型，有400多万例 每年在美国。由于其固有的肿瘤可塑性，BCC具有规避治疗的能力， 实现了令人难以置信的肿瘤进化。肿瘤耐药的非典型途径的识别 极大地影响了对基底细胞癌耐药机制的理解，然而，复杂的肿瘤 异质性产生了巨大的知识鸿沟，这继续阻碍着临床结果。这个 观察到基底细胞癌可以经历向鳞状细胞的肿瘤演变事件(称为路径转换) 细胞癌是一种耐药机制，涉及基因表达的完全改变。 导致癌症类型转换的计划。这项提议的长期目标是阐明分子 以及潜在的途径转换的转录机制，特别强调理解 单细胞分辨率的表观遗传调控。初步数据表明，鳞状细胞癌签名在早期发展 肿瘤进展，这在一定程度上是由于AP-1家族成员转录调控的差异，但 目前还不清楚具体是什么转录因子。因此，这一提议背后的中心假设是 动态表观遗传调控促进BCC中SCC样特征的获得，可能在早期 肿瘤的发展。目标1将揭示推动BCC向SCC发展的关键AP-1家族转录因子(S) 利用一种新的体外系统进行途径切换，该系统可以忠实地模拟这一过程。《目标2》拍摄 原始肿瘤的scRNA-Seq数据集的优势，并提出了额外的scRNA-Seq以及 SCATAC-SEQ实验定义了BCC到SCC途径转换的多组学时间进程。使用 建立了获取新鲜人类BCC肿瘤的渠道，并有能力利用单细胞领域的专业知识 基因组分析表明，本研究在规定的时间内具有较高的可行性。该计划的总体理由是 建议是充分解决临床上未得到满足的需求，以了解基底细胞癌的关键耐药机制。 这一高度创新的方案使用了新的工具，耦合了体外系统来模拟通路切换 患者样本的单细胞基因表达和染色质分析。这项工作很有希望填补一个 关于BCC肿瘤演变机制的重大知识差距，目标是为 更有针对性和更合理的药物疗法。

PROJECT SUMMARY/ABSTRACT: Basal cell carcinoma (BCC) represents the most common type of skin cancer with more than four million cases in the US each year. BCCs have the ability to circumvent therapeutics due to their intrinsic tumor plasticity, allowing for incredible tumor evolution. The identification of non-canonical pathways that drive tumor resistance has dramatically impacted the understanding of BCC resistance mechanisms, however, the complex tumor heterogeneity generates a significant knowledge gap, which continues to hamper clinical outcomes. The observation that BCCs can undergo tumor evolution events (referred to as pathway switching) to squamous cell carcinoma (SCC) represents a resistance mechanism involving complete alterations in gene expression programs leading to cancer-type switching. The long-term goal of this proposal is to elucidate the molecular and transcriptional mechanisms underlying pathway switching with particular emphasis on understanding the epigenetic regulation at single cell resolution. Preliminary data indicate that SCC-signatures develop early in tumor progression, which is in part due to differential transcriptional regulation of AP-1 family members, but what specific transcription factor is not clear. Therefore, the central hypothesis underlying this proposal is that dynamic epigenetic regulation promotes the acquisition of SCC-like features in BCCs, potentially early on in tumor development. Aim 1 will uncover the key AP-1 family transcription factor(s) that drive BCC to SCC pathway switching utilizing a novel in vitro system which can faithfully model this process. Aim 2 takes advantage of scRNA-Seq datasets from naïve tumors and proposes additional scRNA-Seq along with scATAC-Seq experiments to define a multi-omic temporal progression of BCC to SCC pathway switching. With a pipeline to acquire fresh human BCC tumors established and the ability to leverage expertise in single-cell genomic analysis, the proposed research is highly feasible in the allotted time. The overall rationale for the proposal is to adequately address a clinically unmet need to understand a key resistant mechanism in BCC. This highly innovative proposal uses novel tools, coupling an in vitro system to model pathway switching with single cell gene expression and chromatin analysis of patient samples. This work has great promise to fill a significant knowledge gap concerning mechanisms of BCC tumor evolution with goals to clear the path for more targeted and rationale drug therapies.